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Optimizing Anticoagulation Therapy inECMO Patients using Antithrombin III

Item Type text; Electronic Thesis

Authors Oldeen, Molly Elisabeth

Publisher The University of Arizona.

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Link to Item http://hdl.handle.net/10150/228500

http://hdl.handle.net/10150/228500

OPTIMIZING ANTICOAGULATION THERAPY FOR ECMO PATIENTS USING

ANTITHROMBIN III

By

Molly Elisabeth Oldeen

_______________________________________________

Thesis Submitted to the Faculty of the

MEDICAL PHARMACOLOGY DEPARTMENT

In Partial Fulfillment of the Requirements

For the Degree of

MASTER OF SCIENCE

In the Graduate College

THE UNIVERSITY OF ARIZONA 2012

STATEMENT BY AUTHOR

This thesis has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this thesis are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of the material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author.

SIGNED: _________________________________________ Molly Elisabeth Oldeen

APPROVAL BY THESIS DIRECTOR This thesis has been approved on the date shown below:

05/07/12 Douglas F. Larson Date Professor of Pharmacology

3

TABLE OF CONTENTS

LIST OF TABLES ........................................................................................................................5

LIST OF FIGURES.......................................................................................................................6

ABSTRACT ..................................................................................................................................7

BACKGROUND ...........................................................................................................................9

ECMO ...............................................................................................................................................................9

Anticoagulation ........................................................................................................................................................11

Complications Related to ECMO........................................................................................................................14

Coagulation Management....................................................................................................................................17

Previous Research ...............................................................................................................................................19

OBJECTIVES............................................................................................................................. 21

PATIENTS AND METHODS.................................................................................................. 22

Indications for ECMO............................................................................................................................. 22

Anticoagulation and Transfusion Protocols................................................................................ 23

Data Collection and Analysis.............................................................................................................. 23

RESULTS ................................................................................................................................... 25

DISCUSSION............................................................................................................................. 29

CONCLUSIONS......................................................................................................................... 34

Summary..................................................................................................................................................... 34

4

TABLE OF CONTENTS - CONTINUED

Future Directions .................................................................................................................................... 35

APPENDIX ................................................................................................................................ 36

REFERENCES ........................................................................................................................... 44

5

LIST OF FIGURES

Figure 1........................................................................................................................................................ 36

Figure 2 ........................................................................................................................................................................37

Figure 3 ........................................................................................................................................................................38

Figure 4 ........................................................................................................................................................................39

Figure 5 ........................................................................................................................................................................40

Figure 6 ........................................................................................................................................................................41

6

LIST OF TABLES

Table 1 ......................................................................................................................................................... 42

Table 2 ..........................................................................................................................................................................43

7

ABSTRACT

One of the most fundamental aspects of extracorporeal membrane oxygenation

(ECMO) is maintaining proper anticoagulation management in order to prevent

hemorrhagic or thrombotic events. Anticoagulation on ECMO is most commonly

achieved with the use of unfractionated heparin to maintain a minimum

anticoagulation level as monitored by activated clotting time (ACT). Heparin’s main

effect is exerted by binding to and potentiating antithrombin III. Many factors may

contribute to a sub-‐therapeutic ATIII level that may decrease the effectiveness of

heparin. A retrospective record review was performed on all adult ECMO patients

at the University of Arizona Medical Center between 2008 and 2011, in order to

determine optimal ATIII levels for maintaining proper anticoagulation. In addition,

we investigated correlations between ATIII levels and hemorrhagic and/or

thrombotic events. Variables measured include, ACTs, heparin dose, ATIII dose,

ATIII levels, blood product use, and adverse events. Thirty-‐five patients received

ATIII over the course of the ECMO run. Six patients did not receive ATIII and they

were found to have used significantly more blood products than those who did

receive ATIII. Also, heparin dose dropped significantly 24h after the first dose of

ATIII. There is a significant positive correlation between the amount of ATIII given

per day and the amount of packed red blood cells transfused per day. The results

8

suggest an ideal therapeutic range of ATIII dosing, where lack of or too much ATIII

administration can lead to excessive bleeding.

9

BACKGROUND

ECMO

Extracorporeal membrane oxygenation (ECMO) is a form of mechanical

circulatory support that is used in the management of life threatening pulmonary or

cardiac failure. It is often utilized in emergent situations and only for temporary

support. A requirement for extracorporeal membrane oxygenation is systemic

anticoagulation. This happens to be a limitation as well due to bleeding

complications. ECMO controls the gas exchange and perfusion, while stabilizing the

patient physiologically and reducing the risk of iatrogenic injury. Gas exchange can

be dependent on the thickness of the blood film, membrane material, fraction of

inspired oxygen (FIO2), and hemoglobin concentration1. Simultaneously, it allows

time for diagnosis, treatment, and most importantly, recovery from injury or

disease2. Circulation through the device occurs by draining right atrial blood from

the venous circulation through a cannula to an artificial lung device and returning it

to the patient through another cannula to the aorta (veno-‐arterial) or the right

atrium (veno-‐venous). Veno-‐arterial cannulation may provide support for both the

heart and lungs. Veno-‐venous oxygenation is used in series to the native lungs to

assist in oxygenation for those in isolated respiratory failure.

The specific vessel cannulation for both modes of ECMO can vary depending

on the needs of the patient. Veno-‐venous cannulation can be achieved multiple

10

ways through cannulation of the femoral vein and/or internal jugular vein. Veno-‐

arterial cannulation is most commonly through cannulation of the femoral vein and

femoral artery. For infants, with femoral vessels that are too small or difficult to

reach, cannulation is most often via the internal jugular and carotid.

The overall purpose of veno-‐venous cannulation is to return oxygenated

blood to the venous circulation, thereby increasing oxygen content and lowering

CO2 content in the right atrial blood. This blood is pumped through the functionally

preserved cardiac system where the heart is solely responsible for systemic

perfusion and blood flow. Patients remain both sedated and immobile while on this

device. In addition, the lungs are still being ventilated on minimal settings despite

their inability to oxygenate adequately in order to prevent additional damage.

Veno-‐arterial cannulation may provide full or partial cardiac support

depending on the needs of the patient and the underlying function of the heart.

Oxygen and carbon dioxide levels in the blood are a reflection of blood flow that is a

combination of pumping from the heart as well as flow from the circuit. If the lungs

are functioning poorly, then blood leaving the heart from the left ventricle will be

similar to that entering the right atrium. The best location to determine optimal

ECMO flow and measure cerebral perfusion is to take a blood gas from the right

upper extremity. This is because the innominate is the last aortic arch vessel to

11

receive flow from the ECMO circuit when returned retrograde through the femoral

artery.

Clinical syndromes indicated for ECMO include both cardiac and respiratory.

ECMO is reserved for the most medically compromised patients that have exhausted

all optimal care resources and present as a high mortality risk. Acute cardiac failure

occurs when the heart cannot produce adequate cardiac output to supply the body

with oxygenated blood. Acute respiratory failure occurs when the lungs can no

longer efficiently oxygenate the blood and remove carbon dioxide.

Anticoagulation A primary requirement for ECMO is systemic anticoagulation. The most

common drug used to achieve this effect is unfractionated heparin. Heparin is one

of the oldest anticoagulation drugs that is still in clinical use. It did not enter clinical

trials, however, until 1935, for its use as a blood anticoagulant3. Today, it is

commonly used for conditions such as acute coronary syndrome, atrial fibrillation,

deep vein thrombosis, pulmonary embolism, cardiopulmonary bypass for heart

surgery, as well as ECMO4. It continues to dominate anticoagulation therapy for

ECMO because it is rapid acting, easily controllable, inexpensive and widely

available. In addition, it is well tolerated by both adult and pediatric patients5.

12

Heparin is naturally produced by basophils and mast cells. Commercially, it

is most often derived from porcine or bovine sources. Commercial preparations

typically include a wide range of molecular weights from 3,000 to 40,000 Daltons,

with a mean molecular weight of 15,000 Daltons6. The structure of heparin is a

heavily sulfated glycoaminoglycan polymer, making it strongly acidic and negatively

charged. Heparin dosing is primarily dependent on its indication for use.

Cardiopulmonary bypass requires a dose of 300-‐400 U/kg. ECMO requires between

20 and 70 u/kg/h. A unit of heparin is measured as a unit of activity. More

specifically, activity is defined as the “amount of heparin that maintains the fluidity

of 1mL of citrated sheep plasma for 1 hour after recalcification”6. This measurement

technique is used to maintain consistency in dosing as different manufacturers vary

the number of USP units per milligram of drug. Heparin exerts its main effect on the

coagulation cascade. The plasma coagulation cascade is the process of fibrin clot

formation in response to both intrinsic and extrinsic activation. Intrinsic activation

results from contact of blood with foreign surfaces, whereas extrinsic activation

results from injury of the vasculature. Both pathways converge to form the common

pathway, beginning with the activated factor X, which converts prothrombin to

thrombin. Thrombin converts fibrinogen into fibrin, resulting in the formation of a

strong clot after fibrin cross-‐linking. In addition to activating fibrinogen, thrombin

13

also stimulates platelet activation, which results in further platelet aggregation and

adherence to endogenous surfaces forming a strong platelet plug.

Alternatively, in order to prevent excessive clot formation and dissolve clots,

the body has various negative feedback systems. Factors involved include, proteins

C and S, antithrombin III, tissue factor inhibitor and tissue plasminogen activator. It

is here that heparin exerts its main effects.

Heparin specifically provides its pharmacological effects by binding to and

amplifying the enzymatic fuction of antithrombin III (ATIII) by more than 1,000

fold6. Antithrombin III primarily inhibits thrombin, as well activated factor X. It

also inhibits factors IX, XII, and XI, to a lesser extent. The site on heparin that binds

to ATIII is found on about 30% of heparin molecules. In the common pathway,

factor Xa activated the conversion of prothrombin to thrombin which heparin

blocks by binding to antithrombin III. Heparin does have minimal non-‐ATIII

dependent anticoagulation effects. It can bind to and activate cofactor II, a natural

thrombin inhibitor. Biologic activity varies between 30 minutes and 6 hours

depending on systemic heparin concentrations5. Heparin is metabolized by the

reticuloendothelial system in addition to the liver. Up to 50% can be excreted

unchanged by the kidneys. Due to heparin’s half-‐life, patients must be kept on a

constant heparin infusion to maintain anticoagulation, with bolus infusions given as

needed.

14

Some patients may exhibit heparin resistance, which tends to be those who

have had prior heparin therapy or an ATIII deficiency. Small amounts of heparin

may bind to plasma proteins such as vitronectin and fibronectin thereby decreasing

its effectiveness and availability for ATIII7. ATIII levels may also be decreased in

those that have been pretreated with heparin6. If this is the case, it has been shown

that “purified ATIII even in small doses, significantly prolongs the ACT response to

heparin”8. Heparin resistance is also often related to certain clinical conditions such

as sepsis, liver disease, or any condition that exerts stress on the body that may

deplete ATIII levels. Given that many of the critically compromised patients on

ECMO are subject to prior or chronic heparin therapy and have conditions that

induce stress on the body, this is clinically significant. If levels are low to begin with,

prophylactic treatment may be indicated.

There is universal acceptance that ATIII levels fall upon initiation of ECMO,

up to 50% 9, and also, that anticoagulation should be monitored using a combination

of measurement techniques in order to understand the complete coagulation profile

for each individual patient.

Complications Related to ECMO Unfortunately, there are various complications related to ECMO. Most

complications are due to the need for systemic anticoagulation. There is a fine

15

balance to be maintained between excessive anticoagulation resulting in bleeding,

and under dosing resulting in excessive clot formation seen in the circuit tubing or

oxygenator.

Bleeding or hemolysis can occur resulting in the need for replacement and

transfusion of red blood cells. Bleeding can occur at the surgical sites from recent

surgery or at the cannula insertion sites. Unfortunately, this is exacerbated by the

use of heparin as a systemic anticoagulant. For that reason, if a patient is put on

ECMO post-‐operatively, heparin is often withheld until bleeding is controlled.

Hemolysis is another negative side effect of ECMO blood replacement that

may require red blood cell replacement. Fortunately, with further advances in

technology such as low resistance gas exchange devices and second generation

centrifugal pumps, hemolysis is not as common. Hemolysis occurs mainly from

anything resulting in excessive negative pressures and turbulance10. Cavitation can

occur when a fluid such as blood is exposed to an extreme negative pressure in

excess of 650 mmHg. Centrifugal pumps operate at high rpms can cause in excess of

700mmHg negative pressure. This can occur when blood in the pump head is

ejected, but nothing fills the void, therefore a vacuum is created resulting in

cavitation and further hemolysis. Causes of this volume issue can be due to low

blood volume, patient position, cannula size, cannula position, coughing and

others10. This can be a common problem, especially in those post-‐operative patients

16

with excessive bleeding as measured in chest tube output. Volume replacement and

maintaining safe flow parameters are the easiest solutions to avoiding hemolysis.

Other causes of hemolysis are related to shear stress, physical properties of

the ECMO circuit, as well as sub-‐lethal damage to erythrocytes11. As proof of this

hemolysis, the level of plasma free hemoglobin can increase by as much as 10 to 25

fold after just 24 hours of ECMO. Continuous renal replacement therapy, a common

addition to the circuit for those patients in renal failure, is also known to cause

hemolysis, therefore RBC transfusion due to excessive blood loss has a direct

relationship with RBC hemolysis.

Various coagulopathy problems can occur with the use of ECMO as well. Due

to the continuous contact of the patient’s blood volume with the non-‐biologic

surface of the circuit, there is activation of both contact and fibrinolytic systems.

Also, within minutes of initiation of ECMO, there is consumption and dilution of all

factors. Consumption of factors can result in with fewer factors available for

coagulation resulting in bleeding. In a study by Arnold et al., it was found that there

was both evidence of reduction in coagulation factors and activation of the

coagulation cascade12. For this reason, factor replacement is a necessity.

Another complication related to ECMO is clot formation within the circuit.

Clot formation is the most common mechanical complication resulting in potential

thrombus1. This frequently at locations where there is high turbulence such as at

17

tubing connection points as well as in the membrane oxygenator. Severe

consequences to clot formation include passing of clots into to systemic circulation

or oxygenator failure.

Coagulation Management The key to effective anticoagulation in these patients is the utilization of a

variety of monitoring techniques. It is important to create a coagulation profile for

each patient on a daily basis. This includes a combination of laboratory tests such as

measurement of platelet count, antithrombin, aPTT, TEG, as well as hemoglobin

requirements.

The easiest and most popular technique to use is the bedside measurement,

termed activated clotting time (ACT). This measures the integrity of the intrinsic

coagulation and common pathways using a whole blood sample. The acceptable

range for ACT values is between 180-‐220 seconds for patients supported on ECMO.

Despite its continued widespread use due to ease and instant results, ACT has a

limited range of accuracy. Results may be affected by many factors related to

patient characteristics, such as coagulopathy, immature coagulation system (such as

in infants), platelet dysfunction, hypothermia, ATIII levels, age, and hemodilution

from the circuit prime volume5. For this reason, it is important to consult other

monitoring techniques as well.

18

Another common test for anticoagulation management is the

thromboelastogram (TEG). The TEG is useful in that it accurately measures the

viscoelastic properties of a blood sample in order to better understand a patient’s

whole clotting system as opposed to individual components. It describes clot

formation and clot dissolution as part of fibrin breakdown, which is equally

important. The ability to also characterize hypercoagulability is necessary in order

to know if patients have the sufficient clotting factors available or if they need factor

replacement.

Specifically related to the clotting cascade, we are also interested in

measuring activated partial thromboplastin times (aPTT). This is the universal

standard for monitoring heparin therapy, in addition to congenital and acquired

factor deficiencies13. Measuring aPTT alone, however, is not the best indicator of

heparin therapy, as aPTT can be prolonged for many reasons such as factor

deficiencies, vitamin K deficiencies, as well as disseminated intravascular

coagulation. It should be used in combination with the other techniques mentioned

previously.

Despite improvements in the management of ECMO patients, complications

remain high related to bleeding and thrombosis. These patients present a unique

challenge with complicated disease states often involving pre-‐existing clotting

disorders, that are exacerbated by heparin. Therefore, the best approach to reduce

19

incidence of adverse events is multidisciplinary among surgeons, physicians,

perfusionists, nurses and ECMO specialists. To benefit the advancement of patient

care, we present a unique study assessing anticoagulation parameters and outcomes

related to the use of antithrombin III.

Previous Research Currently, there is very little research supporting the topic of anticoagulation

on ECMO specially related to ATIII. Previous studies have explored multiple

coagulation parameters while patients are on ECMO. One particular study

specifically looked at ATIII levels and tested two dosing mechanisms, comparing

bolus versus continuous infusion. They found continuous infusion to show better

overall outcomes by reducing activation of heparin more than bolus infusion14.

They maintained ATIII levels at >100% and showed reduced surgical revision for

bleeding within the first 48 hours. Other studies test for all coagulation factors at

set time points and compare how they relate to patient outcomes14,15. The choice of

using multiple coagulation tests in order to obtain a more accurate picture is that at

times the ACT level alone can be limited due to issues such as consumptive

coagulopathies, clotting factor deficiencies, platelet dysfunction, as well as

fibrinolysis15. Another study measured antithrombin replacement during ECMO

20

and only hemorrhagic complications16, finding that upon administration, there were

no significant differences in bleeding and ATIII levels.

21

OBJECTIVES

This study will be the first to provide a detailed analysis of ATIII and how it

relates to patient outcomes. It will enable us to more effectively manage ECMO

patients and aid in the prevention of adverse events. Hemorrhage will be measured

as packed red blood cell administration and thrombosis will be measured by circuit

change outs or any other evidence of major clotting. At this time, it is uncertain at

what minimum level patients should receive replacement prior to ECMO initiation.

Secondarily, in the long term this project has the possibiility of helping reduce the

costs of ECMO for these patients by preventing circuit change outs caused by

clotting, educing the length of time spent on the assist device, as well as reduce

expensive blood product transfusions.

It is important to monitor ATIII due to the hemodilution and activation of

other factors upon initiation of ECMO. Currently, we measure ATIII levels

throughout the ECMO run. The subsequent drop following initiation can be a

potential hazard towards maintaining optimal anticoagulation. Low levels of ATIII

may produce ACT levels below standard and the administration of more heparin

without sufficient ATIII levels can lead to increased bleeding17. It is also important

to take into consideration preexisting conditions that many patients recommended

for ECMO have that may cause them to have reduced levels of ATIII initially.

22

PATIENTS AND METHODS

An institutional review board-‐approved retrospective chart review was

performed on all adult ECMO patients supported at the University of Arizona

Medical Center between the years of 2008 and 2011.

Indications for ECMO ECMO is indicated for patients that suffer from severe acute cardiac and

respiratory failure. Indications for those that suffer from respiratory failure in this

specific population of patients include syndromes that result in the inability of the

lungs to provide sufficient oxygenation, such as Acute Respiratory Distress

Syndrome (ARDS), H1N1, sepsis, post lung transplantation, and others. Indications

for cardiac failure include syndromes that result in the heart being unable to

provide enough cardiac output or blood supply to the rest of the body, such as,

failure to wean from cardiopulmonary bypass, post myocardial infarction, and

cardiogenic shock. ECMO is used for those patients that have exhausted all other

options for treatment and have an 80% mortality risk2.

The ECMO circuit used at the University of Arizona Medical Center for all

patients includes a Maquet Rotaflow centrifugal pump with the Quadrox heparin

coated hollow fiber membrane oxygenator. Cannulation varied among patients and

23

included (i) intrathoracic, (ii) right internal jugular vein and common carotid artery,

or (iii) femoral vein and artery.

Anticoagulation and Transfusion Protocols Unfractionated heparin was used for anticoagulation purposes for all

patients. Dosing was titrated at drip rates sufficient to maintain an activated

clotting time between 160-‐200 seconds depending on bleeding issues. Packed red

blood cells (pRBCs) were transfused to maintain a hematocrit of greater than 30%.

Platelets and fresh frozen plasma were transfused as needed as well to maintain

normal clotting factor levels.

ATIII levels were measured on all patients to maintain percentage activity

between 80 and 120%. ATIII dosing to maintain normal levels was determined at

the discretion of the physician in combination with manufacturer recommendations.

Data Collection and Analysis Various demographics were collected from patient charts, such as age,

gender, height, weight, and BSA. Indication for ECMO, length of time on ECMO,

survival, and cannulation technique were also collected. Laboratory values included

ACTs, heparin drip rates, ATIII levels, ATIII dosing, as well as blood product use.

24

Adverse events were recorded as bleeding, evidence of clots in the circuit, and

cerebral vascular accidents (CVAs).

In order to determine the effect of ATIII on product use, packed red blood

cells (pRBC), platelets, and fresh frozen plasma transfusions were measured. The

amount of pRBCs transfused was used as a measure of bleeding requiring red blood

cell replacement.

In order to determine the effect that ATIII had on heparin drip rates we

measured heparin infusion at the time of the first dose of ATIII and subsequently 24

hours later. The first dose was used as to avoid potential confounding effects of

multiple doses of ATIII.

25

RESULTS

Throughout the study period, 41 patients were supported on ECMO. One patient

was excluded due to an ECMO duration of only three hours. The patients were

divided into cardiac and respiratory due to the extreme differences in underlying

pathology. The cardiac group (n=21) and respiratory group (n=20), had a

significant difference in ages with a mean age of 57.7 ± 2.7 (mean ± SD) years, and a

mean age of 39.4 ± 3.3 (Table 1) respectively. The cardiac group had a mean weight

of 92 ± 4 kg, and the respiratory group had a mean weight of 84 ± 6 kg. The cardiac

group had a statistically significant shorter length of stay at a mean of 7.4 days,

while the respiratory group had a mean of 14.1 days. Survival differences were also

statistically significant in that the cardiac group had a mean survival rate of 58%,

and the respiratory group had a rate of 35%.

Indications for ECMO in these patients include both cardiac and respiratory

failure disorders. Of the cardiac failure patients (n=21), indications include failure

to wean, idiopathic cardiomyopathy, cardiogenic shock, post cardiac surgery (valve

replacements, root replacements, CABG), post MI, post partum, etc. Of the

respiratory failure patients, a majority of indications for ECMO include ARDS,

respiratory failure, drug overdose, H1N1, sickle cell, pulmonary edema, pulmonary

fibrosis, post lung transplant, etc.

26

When comparing the effect of ATIII on heparin drip rate at first dose and 24h

later, the results show that there is a statistically significant (p< .05) decrease in the

heparin drip rate 24 hours after ATIII was administered (Figure 1). The mean dose

at heparin at ATIII administration was 803 units per hour, which decreased to an

average of 594 units per hour after 24 hours. Six patients were not on heparin

infusions at the time of the first dose of ATIII possibly due to uncontrolled bleeding

post-‐operatively. One of the patients not on heparin infusion had a heparin allergy,

so that patient was excluded as well. For those reasons, analysis was limited to 35

cases.

In comparing those patients who did receive ATIII replacement (n=35) to

those that did not receive ATIII replacement (n=6), there was a significant

difference for all blood products used between those that did not receive any ATIII

and those that did receive ATIII (Figure 2-‐4). Those that did not receive ATIII were

given a mean of 7.02 ± 1.25 units of pRBCs per day, 2.93 ± 0.37 units of platelets per

day, and 4.61 ±1.36 units of FFP per day. This is compared with those who were not

dosed with ATIII that were given 2.81 ± 0.30 units of pRBC per day, 0.77 ± 0.17 units

of platelets per day, and 1.11 ± 0.21 units of FFP per day. The non-‐ATIII group used

significantly more blood products on average per day compared with those who did

receive ATIII.

27

Given that the results suggest ATIII is important, we wanted to determine

how well our institution replacing it, in order to sustain therapeutic levels by

comparing and measuring each group’s ATIII levels post cannulation and the

average ATIII level per day (Table 2). Post cannulation, the cardiac group had an

average ATIII level of 47.7 ± 5.8%, whereas the respiratory group had an average

ATIII level of 67.3 ± 8.2%. The average ATIII level per day was 86.5 ±1.4% for the

cardiac group and 78.1 ±3.1% for the respiratory group. Subsequently, on average,

the patients are being treated to the lower threshold of therapeutic level once

replacement begins. The low levels post-‐cannulation are in support of the findings

that factors are both consumed immediately and slightly hemodiluted.

The cardiac failure group had a significant correlation between the number

of pRBCs transfused per day and the dose of ATIII given per day (p<.05) (Figure 5).

There seemed to be a cluster of patients with less ATIII and less pRBCs possibly

suggesting that there is an ideal amount of ATIII that should be given to avoid blood

product use. On the same graph, there were a few patients with significantly more

ATIII used which correlated with more pRBCs, possibly suggesting that too much

ATIII, an anticoagulant, may result in more bleeding necessitating increased blood

product use. The respiratory group, on the other hand, did not show any significant

correlation (Figure 6) between the amount of blood products used per day and ATIII

units given per day.

28

Adverse events were measured on a nominal scale as yes or no, indicating

whether they were observed throughout the entire ECMO run. There was

suggestive evidence of clotting in 33 (80%) patients. Clotting was visualized on the

circuit itself as dark or white areas most often at the oxygenator or tubing

connection sites. Despite the presence of clotting in many of the circuits, only 13

patients required one or more circuit changeouts throughout the ECMO run.

29

DISCUSSION

The results suggest that antithrombin is, in fact, an important component in

the treatment of ECMO patients. Both high doses and lack of antithrombin III

replacement are correlated with excessive blood product use. There appears to be

a therapeutic range to dose ATIII to prevent bleeding. With this insightful

information, we can continue advance and improve anticoagulation therapy in

ECMO patients.

Other studies have measured the effect of preoperatively treating patients

with ATIII for cardiopulmonary bypass during cardiac surgery. One study by

Avidan, et al., found that treatment with antithrombin III was effective in restoring

heparin effectiveness, in addition to promoting anticoagulation at therapeutic levels

for cardiopulmonary bypass18. Few studies, however, have specifically looked at

ATIII replacement in adult ECMO patients as it correlates with outcomes and blood

product usage. It is recognized that ATIII will continue to be consumed in the

presence of heparin, and there is both hemodilution and activation of clotting

factors from the ECMO circuit. Based on these reasons and the evidence from

previous studies, patients may truly benefit from the maintenance of normal ATIII

activity levels.

As antithrombin is an anticoagulant, it is possible that it can contribute to

increased bleeding in these patients. Our correlation results in the cardiac group (r2

30

= .49) suggested the possibility that too much ATIII may lead to increased RBC

replacement. Other studies have not found that bleeding or the need for pRBC

transfusion increases significantly with ATIII administration16. Further research

with more patients must be conducted to increase the significance of this data.

Our data shows that patients receiving no supplemental ATIII necessitated

significantly more blood products. When trying to understand why this might be

true, we looked at the individual patients. One possible explanation could be that

patient’s heparin dose continued to increase to maintain anticoagulation standards

based on ACTs and the non-‐ATIII dependent anticoagulant effects of heparin

resulted in bleeding. ECMO runs ranged between 2 and 9 days, therefore it was not

a short length of stay that resulted in not receiving ATIII. One patient had a heparin

allergy, which would explain why ATIII was not given to him. That patient was

given argatroban, which is a direct thrombin inhibitor, therefore its use is not

dependent on the presence of ATIII . Almost all patients were placed on ECMO after

extensive heart or lung surgery, such as post lung transplant (two patients), mitral

valve replacement, aortic arch and root replacement (two patients). One patient

was seen post trauma with pulmonary edema.

Further analysis collecting d-‐dimer levels did show elevated levels above the

threshold criteria of <0.5 μg/ml in 5 out of the 6 patients throughout the run. D-‐

dimers are fibrin degradation products that arise from the breakdown of clots

31

degraded by fibrinolysis. Positive d-‐dimer results maybe be suggestive that the

coagulation system has been activated, and a patient is in disseminated

intravascular coagulation (DIC). This is also known as consumptive coagulopathy.

It occurs when the body is rapidly and pathologically activating the coagulation

mechanisms that result in small blood clots in the vessels of the body. The clots

consume all of the clotting factors, which can lead to abnormal bleeding from

locations such as surgical wounds, cannulation sites, etc. Excessive bleeding may

explain why the patients did not receive antithrombin, a natural anticoagulant. It

could be suggested that the traumatic surgery resulted in activation and further

consumption of the clotting factors, leading to increased d-‐dimers as well. When

comparing d-‐dimer levels of patients that did receive ATIII, they had positive levels

as well. This is not surprising as other studies have found elevated d-‐dimer levels at

all times during ECMO despite adequate anticoagulation19.

We also investigated fibrinogen levels. Low levels of fibrinogen can

indicate DIC when fibrinogen is consumed faster than synthesized. It was found that

only 3 of the 6 patients had below threshold fibrinogen levels. Despite the fact that

the presence of d-‐dimers and low fibrinogen levels suggest DIC, more research

would have to be completed to correctly identify these patients as having this

diagnosis that is difficult to identify in general.

32

As expected, we found a significant decrease in heparin drip rates. The

reasoning behind this is that adding ATIII is known to restore heparin’s

effectiveness and to promote therapeutic anticoagulation20. This contrasts with a

similar study that did not find any significant drop in heparin dose or measured ACT

following ATIII administration16. Using less heparin to achieve the adequate

anticoagulation level is beneficial in preventing the potential adverse effects of using

too much heparin. One of the most dangerous complications with the use of heparin

is intracranial brain hemorrhage13.

When looking at the summary statistics between the cardiac and respiratory

group, we noted several significant differences to be interpreted. To begin, the

differences in age were statistically different. One explanation could be that the

older patients are more likely to suffer from the acute heart failure issues that

require them to be placed on ECMO. Also significant were differences between the

lengths of ECMO runs for both groups. Respiratory patients were placed on ECMO

for almost twice as long and survival was significantly lower. Both length of run and

survival may be related to the underlying pathology of these patients. Perhaps

respiratory patients have more irreversible diseases involving their lungs and other

organ systems. It is also possible that the severity of their condition is discovered

too late for ECMO to be of considerable benefit. The cardiac patients possibly suffer

from issues that are more temporary and reversible.

33

The other variables measured did not show statistically significant

differences. There was no significance measured between antithrombin

replacement and ACTs, length of stay, circuit change outs, or the presence of clots in

the circuit. ACTs can be affected by a number of variables which might explain the

wide variability and lack of correlation. More patients would need to be studied in

order to determine any significant results.

This study has various limitations. Being retrospective, it is not possible to

control factors such as whether or not patients receive ATIII, timing and quantity of

dose, and timing of ATIII activity level measurements. ATIII dose was subject to the

attending physician, therefore timing and dose were not necessarily standardized or

consistent. Due to the fact that not all patients were given ATIII on a daily basis, we

had to standardize dosing by dividing the total amount of ATIII given by how many

days the patients were on ECMO. Also, at times the physician recommended dose

would be rounded up to a full vial to reduce waste of an expensive product. In

future use of antithrombin III, it would be beneficial to standardize dosing based on

weight of the patient (kg). Given these patients are very sick, other comorbidities

may be confounding to the results. Obviously, we cannot control the unlimited

number of potential differences between the patient’s etiologies.

34

CONCLUSION

Summary

The management of anticoagulation and bleeding together is a complex issue.

Without sufficient anticoagulation, there can be consumption of coagulation factors

and platelets that can eventually lead to worsening of bleeding16. The present study

suggests that ATIII replacement is necessary while patients are placed on an extra-‐

corporeal membrane oxygenation device. We know that ATIII will consistently be

utilized in the presence of heparin and also that there will be a drop in ATIII due to

hemodilution and factor activation from the circuit. In addition, as the results

suggest, blood product use increases significantly without ATIII administration.

Also, the cardiac group data show that it is possible that excessive ATIII is

associated with blood loss as well as measured by pRBC replacement. For this

reason, we can conclude that there is an ideal therapeutic range for ATIII

administration.

The benefits of this study are widespread. Most importantly, the ability to

reduce bleeding would be beneficial. Reduction in the use of blood products via

reduction in the amount of bleeding is advantageous to the patient by preventing

the potential for transfusion reactions. Finally, reducing blood product use may be a

financial incentive, despite the relatively high cost of antithrombin III.

35

Future Directions

There is great potential for future research to be performed in support of this

data. It would be beneficial to require measurement of ATIII levels pre-‐cannulation

to know what level patients have initially, in order to prevent excessive drops for

reasons discussed previously, in patients that are dependent on heparin. This will

benefit patients that have heparin resistance due to prior heparin therapy, and most

importantly, those with decreased ATIII availability due to liver dysfunction as a

result of sepsis or other disorders. In this way, we can also understand the average

percentage drop in ATIII levels that can be expected from the initiation of ECMO.

Also, establishing a protocol to standardize dosing would be beneficial to evaluate

the effect of ATIII in a prospective manner. To date, no study has been performed to

measure ATIII in ECMO patients, as it has been done successful in cardiopulmonary

bypass patients. Eventually, we can extrapolate our findings to other patients such

as those that are on total artificial heart and ventricular assist devices.

36

APPENDIX

Figure 1. Comparing heparin drip rate at first dose of ATIII and 24 hrs later.

Heparin at Dose

Heparin 24hr After

Mean 803 594.0703704 SE 138.203544 137.3237277

T-test 0.032828587

37

Figure 2. RBC Infusions measured at the units of RBCs given per day compared with ATII Replacement

RBC

NO ATIII ATIII MEAN 7.02 2.81 SEM 1.25 0.30 T-Test 2.20617E-05

38

Figure 3. Platelet Infusions measured at the units of Platelets given per day compared with ATII Replacement

Platelets


39

Figure 4. FFP Infusions measured at the units of FFP given per day compared with ATII Replacement

FFP


40

Figure 5.

41

Figure 6.

42

Table 1. Summary statistics for cardiac and respiratory

Parameter Units Respiratory Cardiac P value n 20 21 ns

Age years 39.4 ± 3.3 57.7 ± 2.7 0.04 Weight Kg 84 ± 6 92 ± 4 ns

BSA M2 1.9 ± 2.0 2.0 ± 0.1 ns Gender % males 50 68 ns Length days 14.1 7.4 0.0383

Survival % 35 58 0.0002

43

Table 2.

ATIII Levels

Average ATIII Post Initiation (%)

Average ATIII Level/day (%)

Cardiac 47.7 ± 5.8 86.5 ± 1.4

Respiratory 67.3 ± 8.2 88.2 ± 5.5

44

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